One child in every 650 live births in this country has a cleft lip and/or palate. This accounts for 13 percent of all reported birth defects, the highest single group of anomalies. The cost of medical care for these children has been estimated to be more than 100 million dollars per year. Present evidence suggests that susceptibility to cleft palate is under polygenic control, and that at least one factor modulating this susceptibility is linked to the major histocompatibility complex (H-2 in mice and HLA in humans) perhaps via its interaction or effects on glucocorticosteroid metabolism and/or receptor proteins. The proposed studies have been designed to (1) confirm the linkage of cleft palate susceptibility in the mouse to the major histocompatibility complex, (2) map the H-2 linked gene(s) modulating this trait, (3) estimate the number of non H-2 genes acting to produce the phenotype, (4) explore the mechanisms through which corticosteroids cause expression of the trait, (5) develop tests to screen human couples for those most at risk to bear children with cleft palate, and (6) identify environmental factors which increase the frequency of cleft palate in the genetically predisposed.